n →π* Interactions Modulate the Disulfide Reduction Potential of Epidithiodiketopiperazines
Name
nihms-1615735.pdf
Description
Accepted version
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1.7 MB
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Unknown
Checksum (MD5)
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Author(s)
Kilgore, Henry R
Olsson, Chase R
D’Angelo, Kyan A
Movassaghi, Mohammad
Raines, Ronald T
Date Issued
September 2020
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Version
Author's final manuscript
Abstract
Copyright © 2020 American Chemical Society. Epithiodiketopiperazines (ETPs) are a structurally complex class of fungal natural products with potent anticancer activity. In ETPs, the diketopiperazine ring is spanned by a disulfide bond that is constrained in a high-energy eclipsed conformation. We employed computational, synthetic, and spectroscopic methods to investigate the physicochemical attributes of this atypical disulfide bond. We find that the disulfide bond is stabilized by two n→π∗ interactions, each with large energies (3-5 kcal/mol). The n→π∗ interactions in ETPs make disulfide reduction much more difficult, endowing stability in physiological environments in a manner that could impact their biological activity. These data reveal a previously unappreciated means to stabilize a disulfide bond and highlight the utility of the n→π∗ interaction in molecular design.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1021/JACS.0C06477
